1,4-bis-(3-indoleglyoxyloyl) piperazines and derivatives thereof

ABSTRACT

THE COMPOUNDS ARE 1,4-BIS (3-INDOLEGLYOXYLOYL) PIPERAZINES. SAID COMPOUNDS ARE USEFUL AS INTERMEDIATES IN THE PREPARATION OF CORRESPONDING 1,4-BIS(2-INDOL-3-YLETHYL)PIPERAZINES AND THEIR SALTS, WHICH ARE PHARMACOLOGICALLY ACTIVE AS HYPOTENSIVES.

' US. Cl. 260-268 United States Patent 3,577,4231,4-BIS-(3-INDOLEGLYOXYLOYL) PIPERAZINES AND DERIVATIVES THEREOF John L.Archibald, Malvem, and Meier E. Freed, Philadelphia, Pa., assignors toAmerican Home Products Corporation, New York, N.Y.

No Drawing. Original application Dec. 3, 1965, Ser. No. 511,362, nowPatent No. 3,471,499, dated Oct. 7, 1969. Divided and this applicationJune 26, 1969, Ser. No.

Int. Cl. C07d 57/100 14 Claims ABSTRACT OF THE DISCLOSURE The compoundsare 1,4-bis-(3-indoleglyoxyloyl)piperazines. Said compounds are usefulas intermediates in the preparation of corresponding1,4-bis(2-indol-3-ylethyl)piperazines and their salts, which arepharmacologically active as hypotensives.

This application is a division of US. Ser. No. 511,362, which was filedon Dec. 3, 1965, and is now US. Patent No. 3,471,499 granted Oct. 7,1969.

This invention relates to chemical compounds that are derivatives ofpiperazine, and, more particularly, to 1,4- bis-(2-indol-3-yl-ethyl)-piperazines, their salts, and method of producing them.

The compounds of the invention, in the form of the free bases, may berepresented by the general formula:

wherein R, R R and R each may be hydrogen or lower alkyl, and adjacent Rand R or R and R may be joined so as to form a second ring; n may be aninteger from 0 to 1; Z and Z' each may be glyoxyloyl or an alkylenechain of either two or three carbons and which may be optionallysubstituted by lower alkyl either adjacent to the indole moiety or tothe junction with the piperazine ring; R and R each may be hydrogen orlower alkyl; W and W each may be hydrogen, lower alkyl or aralkyl; and Xand X' may be hydrogen, alkyl, alkoxy, halogen, trihalomethyl orhydroxy.

It has been discovered that compounds of this invention meeting thedescribed qualifications whether as free bases or the acid-additionsalts thereof, demonstrate at least one, but often multiplepharmacological activities, when Z and Z of Formula I above are selectedto be alkylene. Thus, said compounds of this invention have been foundto be "ice useful for their pharmacological activity as hypotensivesand/ or central nervous system depressants. Compounds of the inventionmeeting said qualifications, but having Z and Z of said Formula I aboveas glyoxyloyl, have been found to be valuable intermediates useful forpreparing said compounds of the invention which have the statedpharmacological activities.

In preparing the piperazine derivatives of the present invention, thefree bases may most generally and conveniently be prepared by preparing,from a suitable indole and oxalyl chloride, the corresponding gloxyloylchloride, and then reacting with the resulting 3-indolyl gloxyloylchloride, the piperazine derivative, in an inert organic solvent; toobtain the desired 1,4-bis(indolylgloxyloyl)piperazine derivative. Saidderivative may then be reduced by conventional means, such as the use oflithium aluminum hydride, to obtain the desired final compounds of theinvention. Alternatively, the 3-indolylalkyl carboxylic acid may bereacted directly with a suitable piperazine derivative (optionally inthe presence of dicyclohexylcarbodimide) and the resulting1,4-bis(indolylgloxyloyl)piperazine derivative again reduced to theresulting desired compound of the invention by conventional means, as inthe first referred-to method. In certain instances, the compounds of theinvention may be prepared by reacting an N,N bis(indol 3 (lower)alkyl)alkylenediamine with oXalyl chloride to result in ring closure with theformation of a 2,3-diketo piperazine derivative, which may then bereduced to the desired compounds of the invention with conventionalreduction catalysts. In accordance with the invention, thealkylenediamine intermediate may consist of an ethylene or propylenechain with an alkyl substitution on one of the carbon atoms thereof soas to result in such substitution on the resulting piperazine nucleus.Instead of utilizing oxalyl chloride; chloroacetylchloride, or thecorresponding ethyl ester, may be utilized for obtaining a2-ketopiperazine nucleus with also the possibility of a 3-alkylsubstituent thereon by utilizing, as the chloroacetylchloride orcorresponding ethyl ester, one having the desired alkyl substitution onthe at carbon atom thereof. The compounds of the invention may also beprepared by reaction of an indol-3-yl ethyl halide or sulfonic acidester with piperazine. 'In certain instances, the compounds of theinvention may be prepared by utilization of the Fisher indole-synthesisreaction by employing a 1,4-bis(4-ketopentyl)-piperazine withphenylhydrazine (or a ring substituted derivative thereof) underreducing conditions, to result in the compounds of the invention,wherein R and R are methyl-substituted, and X and X may each be thesubstituent furnished by the phenylhydrazine reactant. Substituents Wand W may be introduced after compound formation by alkylation of thesodium salt of said compound.

The routes of preparation described above are indicated schematicallybelow, wherein, in all cases Indrepresents indol-3-yl.

I ll 0 O 0 O C 2- Cl-iZ-O-Cl [I Plperazine I I 1 L1AlH 1. Ind-H 11cm IdInd-C- -01 Ind-C- -N J xay on e Ind-0112011216 NOH2OH -Ind D" lb 1 2IHG-CHZCOZH (ciiis infii e h n Lnnrn Ind-CHzC-N N-C--CH -Ind orInd-CIh-C 0 01 Piperazine X =halogen or sulfonle acid ester i N NH Li .N7. X (CH2) TGX' WE) 4 Ra 2 at f t H H R, R R2, R3, R4, R, X, X, w, w Zand Z each have the meaning as l given herelnbcfore R R1 Z-N NZ' X cm Xl 3 2 \N/-R R R R5 N v'v vv' Many of the reactants employed in theprocesses of this Wh th compounds of h i ti are employed inve tio arknown Compounds Which are reudily ayailas hypotensives and/ or centralnervous system depressants, able from commercial sources. Others whichare not comthey may b d i i d alone or i bi ti ith mercially availablecan be prepared in accordance with pharmaceutically acceptable carriers,the proportion of standard organic procedures which are known to thosewhich is determined by the solubility and chemical nature skilledintheart. of the compound, chosen route of administration and Compoundsfalling within the scope of the formula as stehdaro Pharmaceuticalpractice For P y may given above, may be used in the form of theiracid-addibe fidmlhlstel'ed o y v111 h form Pt tablets o capsules tionsalts while still retaining their pharmacological ef- Whleh h y eohtalheollvehtlohat eXCIPIeBtS, 111 the h fectiveness. The salts provide greatflexibility in therapeuo solutlohs; h y y be lhleeted Parehterahy, that18 tic use since they may impart various degrees f Watermtramuscularly,intravenously or subcutaneously. For solubility to an otherwisesubstantially insoluble base. Parenteral aolhlhlstr ou y y be used 111the form of With regard to the acid-addition salts, as is well known inSterne solutlohs oontalhlng other solutes; eXaIhPIe, the pharmaceuticalart, either Organic or inorganic acids enough saline or glucose to makethe solutions 1sotonic. may be used as long as they do not substantiallyincrease The dosage of the present therapeutic agents will vary thetoxicity of the compounds. For example, the comwith the form ofadministration and the particular compounds which are useful as basesper so may be used in the pound chosen. It will generally be found thatWhen the form of their salts with suitable organic acids including 5composition is administered orally, larger quantities of the acetic,propionic, tartaric, citric, and the like, or inorganic active agentwill be required to produce the same eflEect acids includinghydrochloric, hydrobromic, sulfuric, phosas a Smaller q n y g nparenterally. In general, the phoric, and h lik compounds of thisinvention are most desirably admin- The acid-addition salts may beprepared by procedures istered at a concentration level that Willgenerally afford w ll know to th kill d i th m F l effective resultswithout causing any harmful or deleterious a selected novel free base ofthe invention may generally Side efieets and Preferably at a level thatis in the range of be dissolved in a suitable solvent and the selectedacid from about to about 15 g- P g. of body may then be added thereto.Since the preparation of acid- Weight p y, although as aforemeutiohedVariations addition salts is well known, it need not be described inwill occur. However, a dosage level that is in the range any greaterdetail here. of from about 0.2 mg. to about 5 mg. per kg. of body weightper day is most desirably employed in order to achieve effectiveresults.

The following examples are given by way of illustration.

EXAMPLE I (a) 1,4-bis (3 -indoleglyoxyloyl) -piperazine Piperazine (2.6g. in dry 1,2-dimethoxyethane (100 ml.) Was stirred while3-indoleglyoxyloyl chloride (4.2 g.) in 1,2-dimethoxyethane (25 ml.) wasadded dropwise. The resulting precipitate was collected, suspended inwater and stirred for 30 min. then collected again, washed well withWater and dried to give 4.3 g. of a colorless solid, M.P. 360. Tworecrystallizations from dimethylformamide-water gave the product, M.P.360.

Analysis.Calcd. for C H 'N O4 (percent): C, 67.28; H, 4.71; N, 13.08.Found (percent): C, 66.69; H, 4.67; N, 13.24.

(b) 1,4-bis (2-indol-3-y1ethyl)piperazine Compound (a) (1.0 g.) wassuspended in dry 1,2-dimethoxyethane (100 ml.) and lithium aluminumhydride (l g.) was added. The mixture was stirred and refluxed for 24hrs. then cooled in an ice bath. Excess lithium aluminum hydride wasdecomposed by the dropwise addition of water. The granular inorganicmaterial was filtered off and the filtrate was evaporated in vacuo togive a colorless oil with strong blue fluorescence. The oil crystallizedon scratching and was recrystallized from ethanol-water to provide theproduct as colorless needles (0.6 g.) M.P. 1967.

Analysis.Calcd. for C H N (percent): C, 77.38; H, 7.58; N, 15.04. Found(percent): C, 77.12; H, 7.60; N, 14.81.

EXAMPLE II (a) Hexahydro-1,4-bis( 3-indoleglyoxyloyl lH-1,4-diazepineHomopiperazine was treated with 3-indoleglyoxy1oyl chloride in1,2-dimethoxyethane in the same way as in Example I(a).Recrystallization of the crude material from aqueous dimethylformamidegave the product as colorless microprisms M.P. 330 (decomp.).

Analysis.Calcd. for C H N O (percent): C, 67.86; H, 5.01; N, 12.66.Found (percent): C, 67.95; H, 5.19; N. 12.63.

(b) Hexahydro-,4-bis(2-indol-3-ylethyl)-1H-1,4-diazopine The compound ofExample II(a) was reduced with lithium aluminum hydride in refluxing1,2-dimethoxyethane as in Example I(b) and worked up in the same way togive the crude product as a colorless oil. The oil was dissolved inether, filtered and cooled in an ice-bath. Ethereal hydrogen chloridewas added until just acid and the precipitated hydrochloride wascollected. It was conver-ted back to the base by stirring withchloroform-% sodium hydroxide solution. The chloroform layer was washed,dried, and evaporated and the resulting foam was crystallized frombenzene. Recrystallization from benzene, then from ether, gave theproduct, M.P. 107-8".

Analysis.--Ca1cd. for C H N (percent): C, 77.68; H, 7.82; N, 14.50.Found (percent): C, 77.58; H, 7.81; N, 14.33.

EXAMPLE III (a) 1,4-bis 3-indoleg1yoxyloyl) -trans-2,5-dimethylpiperazine A solution of 3-indoleglyoxyloyl chloride (20.8g.) in 1,2-dimethoxyethane (250 ml.) was added during 10min. to astirred mixture of trans-2,5-dimethylpiperazine (16.8 g.) in1,2-dimethoxyethane (150 ml.). After standing overnight, the precipitatewas collected, washed very thoroughly with water and dried, giving acolorless solid (20 g.) MJP. 358 (d.). Rercrystallization fromdimethylformamide gave the product (17.4 g.), M.P. 361-2".

6 Analysis.Calcd. for C H N O (percent): C, 68.41; H, 5.30; N, 12.27.Found (percent): 68.92; H, 5.00; N, 12.17.

(b) 1,4-bis 2-indol-3-ylethyl) -trans- 2,5-dimethylpiperazine Theforegoing product (15 g.) and lithium aluminum hydride (7.5 g.) in dry1,2-dimethoxyethane (500 ml.) was stirred under reflux for 18 hr. thencooled in an ice bath and decomposed with water (25 ml.). The mixturewas filtered and the filtrate was evaporated. Recrystallization of theresidue from N,N-dirnethylacetamide provided the product (10.0 g.) M.P.202-4.

Analysis.-Calcd. C H N (percent): C, 77.79; H, 8.05; N, 13.99. Found(percent): C, 77.72; H, 7.98; N, 13.82.

EXAMPLE IV (a) l,4-bis( 3-indoleglyoxyloyl) -cis- 2,5-dimethylpiperazineThis compound was prepared from cis-2,5-dimethylpiperazine and3-indoleglyoxyloyl chloride by a procedure similar to those used inExamples 1(a), H(a), and III(a). After two recrystallizations fromN,N-dimethylacetamide-water, the product had M.P. 3379 (decomp.).

(b) 1,4-bis (2-indol-3 -ylethyl) -cis- 2,5-dimethylpiperazine Reductionof the foregoing product was carried out in essentially the same Way asin the previous examples. The crude material was recrystallized firstfrom ether, then from aqueous ethanol, to give the product as colorlessprisms M.P. 157-43".

Analysis.Calcd. for C H N (percent): C, 77.96; H, 8.05; N, 13.99. Found(percent): C, 77.47; H, 8.00; N, 14.11.

EXAMPLE V The procedures of Example 1(a) and (b) are repeated utilizingeach of the following indoleglyoxyloyl halide derivatives as reactantsfor separate reaction with piperazine, followed by reduction in thepresence of lithium aluminum. hydride to produce the hereinafter listedproducts, respectively:

The title compound was prepared in the manner of Example IV(a), byutilizing 5-methoxyindole-3-glyoxyloyl chloride in place of3-indoleglyoxyloyl chloride. Crystallized from aqueousdimethylformamide, the product had an M.P. 297-300" (dec.).

Analysis.Calcd. for C H N O (percent): C, 65.10; H, 5.46; N, 10.85.Found (percent): C,64.83; H, 5.39; N, 10.90.

7 EXAMPLE VII Using the same general procedure of Example I( a) and (b),as followed in Example VI, the 3-indoleglyoxyloyl halides and piperazinecompounds are employed as reactants, and the resulting products reducedto obtain the respective products, as given below:

Reactants Final product z-methyl-indole-3-ylglyoxyloyl- 1 ,4-bis(2-[2-methyl lndol-3-yl1 chloride and2,6-dimethy1plperethyl)-2,6-dimethylp1peraz1ne. azlne.l-methyl-lndol-3:ylglyoxyloyl 1,4-bis (2-[1-methyl-lndol-3-y1] chlorideand c1s-2-methyl-5- ethyl)-cls-2-methyl-5-ethyl ethylpiperazme.piperazine.

7-methylindol-3-ylglyoxyloyl chloride and eis-2,5-dimethylpipera- Z1116.

fi-bromoindol-S-ylglyoxyloyl ch10- r10}; and cis-2,5-dnnethy1-p1peraz e.

1 ,4-bis-2- (7-methylindol-3-yl) ethyl-cis-2,5-dimethylpiperamne-1,4-bia-2-(5-bromoindol-3-y1) ethy1-cis-2,fi-dimethylpiperazine.

EXAMPLE VIII 1,4-bis(3-indoleglyoxyloyl)-1,2,3,4-tetrahydroquinoxalineFollowing the procedure of Example I(a), 3-indoleglyoxyloyl chloride and1,2,3,4 tetrahydroquinoxaline were reacted to form the title compoundwhich was. crystallized from aqueous dimethylformamide as a D.M.F.solvate, M.P. 290.

Analysis.-Calcd. for C28H20N4O4.C3H7NO (percent): C, 67.75; H, 4.95; N,12.40. Found (percent): C, 67.77; H, 4.64; N, 12.05.

EXAMPLE 1X l,2,3,4-tetrahydro-1,4-bis[2-(3-indolyl)ethyl]- quinoxalineFollowing the procedure referred to in Example VII, the product ofExample VIII was reduced to obtain the title compound having an M.P.175-6".

Analysis.-Calcd. for C H N (percent): C, 79.96; H, 6.71; N, 13.32. Found(percent): C, 79.98; H, 6.81; N, 13.62.

EXAMPLE X 1,4-bis (2-methylindole-3 -glyoxyloyl) piperazine Using theprocedure of Example I(a), 2-methylindole- 3-glyoxyloyl chloride andpiperazine were reacted to obtain the title compound having an M.P. 3456(dec.).

Analysis.-Calcd. for C H N O (percent): C, 68.41; H, 5.30; N, 12.27.Found (percent): C, 68.38; H, 5.13; N, 12.27.

EXAMPLE X'I 1,4-bis[2-(2-methyl-3-indoly1) ethyl] -piperazine Theproduct of Example X was reduced and the product was crystallized fromaqueous dimethylformamide to obtain the title compound, having an M.P.240-243".

Analysis.Calcd. for C H N (percent): C, 77.96; H, 8.05; N, 13.99. Found(percent): C, 77.54; H, 8.27; N, 13.76.

EXAMPLE XII 1,4-bis (2-methylindole-3 -glyoxyloy1) cis-2,5-dimethylpiperazine Following the reaction procedure, as in Example X,but substituting cis-2,S-dimethylpiperazine for piperazine, the titlecompound was crystallized from aqueous dimethylformamide and had an M.P.342-3" (dec.).

Analysis.--Calcd. for C H N O (percent): C, 69.40; H, 5.83; N, 11.56.Found (percent): C, 69.18; H, 5.79; N, 11.80. l

8 EXAMPLE XIII 1,4 bis [2- 2-methylindolyl) ethyl] -cis-2,5-dimethylpiperazine The title compound was obtained by reduction of theproduct of Example XII. The new compound was crystallized from aqueousdimethylformamide as colorless prisms, M.P. 182-208.

Analysis.Calcd. for C H N (percent): C, 78.46; H, 8.47; N, 13.07. Found(percent): C, 78.49; H, 8.53; N, 12.87.

EXAMPLE XIV l,4-bis(3-indoleglyoxyloyl) -2,6-dirnethylpiperazine Thetitle compound was prepared as in Examples I(a), but substituting2,6-dimethylpiperazine for piperazine. Crystallized from aqueousdimethylformamide, the title compound had an M.P. 342-3" (dec.).

Analysis.--Calcd. for C H N O, (percent): C, 68.41; H, 5.30; N, 12.27.Found (percent): C, 68.17; H, 5.47; N, 12.36.

EXAMPLE XV 1,4-bis[2-(3-indolyl)ethyl] -2,6-dimethylpiperazine Obtainedby reduction of the compound of Example XIV, the new compoundcrystallized from ethanol, M.P. 174-6".

Analysis.Calcd. for C H N (percent): C, 77.96; H, 8.05; N, 13.99. Found(percent): C, 77.60; H, 8.39; N, 13.62.

EXAMPLE XVI 1,4-bis (3-indoleglyoxyloyl) -2,3,5,6-tetramethy1-piperazine 1,4-bis 3-indolyl) ethyl] -2,3,5,6-tetramethylpiperazine Thecompound of Example XVI was reduced and the resulting product wasisolated as fumarate salt, monohydrate, M.P. -105 Analysis.Calcd. forC23H36N4.C4H404.H2O (Pfircent): C, 68.30; H, 7.52; N, 9.96. Found(percent): C, 68.85; H, 7.47; N, 10.27.

EXAMPLE XVIII 1,4-bis (3 -indoleglyoxyloyl) -2-methylpiperazine Thetitle compound was prepared in the same Way as that of Example I(a), bututilizing 2-methylpiperazine in place of piperazine. The compound oncrystallization from aqueous dimethylformamide, had an M.P. 348-5 0(dec.).

Analysis.Calcd. C H N O (percent): C, 67.86; H, 5.01; N, 12.66. Found(percent): C, 67.62; H, 5.29; N, 12.67.

EXAMPLE XIX 1,4-bis [2- 3 -indolyl) ethyl] -2-methylpiperazine Byreduction of the product of Example XVIII, the title compound wasobtained. It was recrystallized three times from aqueous ethanol, M.P.107.

Analysis.-Calcd. for C H O (percent): C, 77.68; g, 7218;; N, 14.50.Found (percent): C, 77.57; H, 7.51;

9 EXAMPLE XX 1,4-bis -bromoindole-3-glyoxyloyl -piperazine The titlecompound was prepared by the procedure of Example 1(a), utilizing5-bromoindole-3-glyoxyloyl chloride in place of 3-indoleglyoxyloylchloride. The resulting product was crystallized from aqueousdimethylformamide and had an M.P. 360.

Analysis.-Calcd. for C H Br N O' (percent): C, 49.18; H, 3.09; N, 9.66,Br, 27.27. Found (percent): C, 49.15; H, 2.97; N, 9.47; Br, 27.3.

EXAMPLE XXI 1,4-bis-(5-methoxyindole-3-glyoxyloyl)-piperazine Againfollowing Example I(a), but utilizing S-methoxyindole-3-glyoxyloylchloride in place of 3-indoleglyoxyloyl chloride, the title product wasobtained and crystallized from aqueous dimethylformamide as ahemihydrate, M.P. 365 (dec.).

Analysis.Calcd. for C26H24N4O6-1/2 H20 (percent): C, 62.76; H, 5.06; N,11.25. Found (percent): C, 62.65; H, 5.04; N, 11.47.

EXAMPLE XXII 1,4-bis [2- 5-methoxy-3-indolyl) ethyl] -piperazineObtained by reduction of the product of Example XXI, the title compoundcrystallized from aqueous dimethylformamide, M.P. 21011.

Analysis.-Calcd. for C H O N (percent): C, 72.19; H, 7.46; N, 12.95.Found (percent): C, 72.41; H, 7.60; N, 12.86.

EXAMPLE XXIII 1,4-bis[2-( l-methyl-3-indolyl)ethyl1-piperazine Thecompound obtained in Example I(b) (7.46 g.) was added to a stirredsolution of sodium amide in liquid ammonia (ca. 500 ml.) prepared fromsodium (1.10 g.) and liquid ammonia. Methyl iodide (5.8 g.) in ether(100 ml.) was added dropwise to the stirred mixture; then the ammoniawas allowed to evaporate overnight. Ether (200 ml.) was added to theresidue, followed by water (200 ml. added dropwise at first).

The insoluble material was filtered 01f and dried to give 5.7 g. Asecond crop (1.3 g.) was obtained from the ether layer. Tworecrystallizations from ethanol gave the title product as colernessneedles, M.P. 12931.

Analysis.-Calcd. for C H N (percent): C, 77.96; H, 8.05; N, 13.99. Found(percent): C, 78.22; H, 8.21; N, 14.05.

EXAMPLE XXIV 1,3-bis [2- 1-methyl-3-indolyl) ether] -cis-2,5-dimethylpiperazine Starting with the product of Example IV(b), the titlecompound was obtained by the procedure of Example XXIII. It crystallizedfrom hexane as colorless needles, M.P. 81-4".

Analysis.-Calcd. for C H N (percent): C, 78.46; H, 8.47; N, 13.07. Found(percent): C, 78.79; H, 8.30; N, 12.82.

EXAMPLE XXV 1,4-bis 2-( 1-ethyl-3-indolyl) ethyl] piperazine Againfollowing the procedure of Example XXIII, but utilizing ethyl iodide inplace of methyl iodide; the title compound crystallized from ethanol ascolorless prisms, M.P. 125-7".

Analysis.Calcd. for C H N (percent): C, 78.46; H, 8.47; N, 13.07. Found(percent): C, 78.18; H, 8.18; N, 12.82.

EXAMPLE XXVI 1,4-bis [2- l-benzyl-B-indolyl) ether] piperazine The titlecompound was prepared by a procedure similar to that of Example XXIII,by utilizing benzyl bromide 10 in place of methyl iodide. The finalproduct crystallized from ethyl acetate as colorless needles M.P.l58-161. Analysis.-Calcd. for C H N (percent): C, 82.57; H, 7.29; N,10.14. Found (percent): C, 82.30; H, 7.60; N, 10.43.

EXAMPLE XXVII 1,4-bis [2-( 1,2-dimethyl-3 -indolyl) ether] -cis-2,5-dimethylpiperazine Starting with the product of Example XIII, the titlecompound was obtained by a procedure similar to that of Example XXIII.Crystallized from aqueous dimethylformamide as colorless prisms, theproduct had an M.P. 176-8.

Analysis.Calcd. for C H N (percent): C, 78.90; H, 8.83; N, 12.27. Found(percent): C, 78.84; H, 9.10; N, 12.01.

EXAMPLE XXVIII 1,4-bis(2-indol-3-ylethyl) piperazine o 0 0 o t... .44 X(CHz)u- X1 R3 vv wherein R, R R and R are each selected from the groupconsisting of hydrogen and methyl; n is an integer from 0 to 1; R and Rare the same and are selected from the group consisting of hydrogen,methyl and ethyl; W and W are the same and are selected from the groupconsisting of hydrogen, lower alkyl containing from 1 to 3 carbon atoms,phenethyl and benzyl; and X and X are the same and are selected from thegroup consisting of hydrogen, lower alkyl containing from 1 to 3 carbonatoms, lower alkoxy containing from 1 to 3 carbon atoms, halogen,trihalomethyl and bydroxy. 2. A compound as defined in claim 1 which is:1,4- bis 3 -indoleglyoxylyl -piperazine.

3. A compound as defined in claim 1 which is:hexahydro-l,4,-bis(3-indoleglyoxylyl)-1H-1,4-diazepine.

4. A compound as defined in claim 1 which is: 1,4- bis 3-indoleglyoxyly1-trans-2,S-dimethylpiperazine.

5. A compound as defined in claim 1 which is: 1,4-bis-(3-indoleglyoxylyl)-cis-2,S-dimethylpiperazine.

6. A compound which is: 1,4-bis,3-indoleglyoxyloyl)-1,2,3,4-tetrahydroquinoxaline.

7. A compound as defined in claim 1 which is: 1,4-bis(2-methylindole-3-glyoxyloyl)piperazine.

8. A compound as defined in claim 1 which is: 1,4-bis(2-methylindole-3-glyoxyloyl)cis-2,S-dimethylpiperazine.

9. A compound as defined in claim 1 which is: 1,4- References Cited bis3-indoleglyoxyloyl) -2,6-dimethylpiperazine.

10. A compound as defined in claim 1 which is: 1,4- UNITED STATESPATENTS bis(3-indoleglyoxyloy1)-2,3,5,6-tetramethylpiperazine. 23704621/1957 Speeter at 260-288X 11. A compound as defined in claim 1 whichis: 1,4- 5 2909523 10/1959 Bach et 260*268bis(3-indoleglyoxyloy1)-2-methylpiperazine. 3,030,363 4/1962 P 260*268X12. A compound as defined in claim 1 which is: 1,4- 3,051,710 8/1962B161 260-268 bis(5-bromoindole-3-glyoxyloyl)-piperazine. 3,188,3136/1965 Archer 260fi268 13. A compound as defined in claim 1 which is:1,4- 3,328,406 6/1967 Wolf 260 268 bis-(5-methoxyindole-3-glyoxyloyl)-piperazine. 10

14. A compound as defined in claim 1 which is: 1,4- DONALD DAUS PnmaryExammer bis(5 methoxyindole 3 glyoxyloyl) cis 2,5 di- U.S. Cl. X.R.

methylpiperazine. 260239, 250

